Cognitive impairment in chronic kidney disease (CKD) patients impacts up to 12 million US adults and is a major public health problem. The mechanisms that underlie cognitive changes in CKD are unknown; however, the rates of cognitive impairment increase with worsening kidney function, suggesting an association between kidney function and cognitive impairment. While vascular disease is highly prevalent in CKD, and a greater proportion of cognitive impairment has been attributed to vascular causes in CKD, traditional cardiovascular risk factors do not account for the higher risk of cognitive impairment in CKD compared to those without CKD. Preliminary data from our lab and others demonstrates that biomarkers of inflammation (C-reactive protein, Interleukin-6), hemostasis (factor VIII, D-dimer and fibrinogen) and endothelial activation (E-selectin, Vascular cell adhesion molecule-1, Intercellular adhesion molecule-1) are linked to both CKD and cognitive impairment independently. As candidate biomarkers in the pathway between CKD and cognitive impairment, we hypothesize that these biomarkers mediate cognitive impairment in CKD. In addition, little is known about the trajectory of cognitive function in persons with CKD, as most previous studies have focused on cross-sectional associations. To address these knowledge gaps, we will study participants in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study. We have repeated measures of global cognitive function annually and a cognitive battery biannually in a sample of 23,183 black and white adults from across the U.S., 9% of whom have CKD. Our overall hypothesis is that cognitive decline in CKD is progressive and that there are unique trajectories and biomarkers of cognitive impairment. In this project, we aim to 1) Characterize the trajectories of cognitive impairment in CKD among a nationally representative sample and the risk factors for different trajectories, and 2) Determine the role of activation of inflammation, hemostasis and endothelium in the association of CKD and cognitive impairment. The innovative aspects of our study include a) the REGARDS study as a unique, longitudinal dataset with measures of global cognitive function and a cognitive battery of tests on learning, verbal memory and executive function, b) the use of group-based trajectory modeling to distinguish different trajectories of cognitive function and identify risk factors for rapid decline, and c) the ability to measure, in a sub-cohort of 4,000 participants, new analytes reflecting potential mediators of cognitive decline in CKD including inflammation, hemostatic and endothelial activation. The results of our study will determine the natural history of cognitive decline in CKD, shed light on vascular mechanisms of CI in CKD, a critical area of brain health research, and will lay the groundwork for future interventions to reduce cognitive impairment in CKD.